MA affects the central nervous system (CNS) by releasing monoamine neurotransmitters such as dopamine, norepinephrine, and serotonin. Administration of MA leads to many pharmacological effects due to its ability to use various molecular processes.[1] MA increases levels of monoamines by forcing the monoamines out of their storage vesicles and expelling them into the synaptic gap by making the dopamine transporters work in reverse.[2] Other mechanisms by which methamphetamine are known to increase monoamine levels are by:

Blocking the reuptake of monoamines by inhibiting the activity of monoamine transporters

Decreasing the expression of dopamine transporters at the cell surface

Increasing cytosolic levels of monoamines by inhibiting the activity of monoamine oxidase (MAO)

Increasing the activity and expression of the dopamine-synthesizing enzyme tyrosine hydroxylase (TH)

In addition to releasing potent amounts of monoamines, MA has a high lipid solubility that leads to a relatively fast transfer of the drug across the blood brain barrier.[1]Click here to see an animation on how MA works in the brain.(activate the animation by clicking on “without amphetamine” “reload” or “with amphetamine”)

Timing of Effects

Injecting or smoking MA results in an almost instantaneous euphoric sensation that lasts several minutes and is described by users as a “rush;” this is then followed by a “high” (a less intense euphoric effect) that can last for hours. When users smoke methamphetamine, it is taken directly to the pulmonary vascular bed which has a large surface area and can absorb the drug quickly.[3,4] Smoking, consequently, approximates injecting in terms of delivering the drug to the brain.

Unlike injecting and smoking, snorting or oral consumption do not produce a rush. They do, however, produce a high that lasts longer than the high associated with smoking and injecting, possibly because snorting and oral administration result in slower and thus lengthier, absorption.[5]

Metabolism

The liver is primarily responsible for the breakdown of MA. The drug undergoes oxidation and glucuronidation in the liver creating amphetamine, norephedrine, and p-hydroxynorephedrine. The oxidation of MA to amphetamine is partly done by cytochrome P-450 (CYP) isoenzyme 2D6. The elimination half-life (t-1/2) of MA is dependent on the urine pH. When urine pH is six to eight, the half-life is about 12 hours, staying constant and unaffected by the route of administration.[6]